A PTP4A3 inhibitor for SARS-CoV-2-mediated acute lung injury

严重急性呼吸系统综合症冠状病毒(SARS-CoV-2)是目前 新冠肺炎大流行。SARS-CoV-2和其他冠状病毒一样，感染人的呼吸道，并通过其S进入细胞 (Spike)蛋白，与人血管紧张素转换酶2(ACE2)结合，并由宿主启动 丝氨酸蛋白酶TMPRSS2。在肺微血管上观察到ACE2和TMPRSS2 上皮和内皮细胞。部分新冠肺炎患者出现急性呼吸窘迫综合征 (ARDS)以及随后的感染性休克和多器官衰竭；大约一半将死亡。慢性阻塞性肺疾病的临床恶化 新冠肺炎的后期阶段被认为是由于刺激性蛋白与肺微血管结合所致 内皮和上皮会导致呼吸道受损，最终导致全身性炎症 反应或细胞因子风暴。目前还没有FDA批准的治疗肺源性心脏病的药物/疗法 与新冠肺炎相关的损害和ARDS。KeViRx正在提议开发一种全新的治疗方法 预防或减轻最初的肺损伤并阻止致命的细胞因子风暴的策略。 我们的先导化合物KVX-053是一种可逆的、选择性的、变构的PTP4A3磷酸酶抑制剂， 良好的体内药代动力学特性和类药物特性。此外，小鼠耐受多个 接触KVX-053。在体外培养条件下，KVX-053对人卵巢上皮细胞和成纤维细胞无细胞毒性。 浓度高达25微米。令人惊讶的是，我们发现KVX-053显著增强了肺组织 细菌脂多糖和血管损伤前后的微血管屏障功能 内皮生长因子。已知PTP4A3磷酸酶在SARS-CoV后12小时在肺细胞中被诱导 感染和控制细胞因子的释放。此第一阶段SBIR应用的总体假设是 PTP4A磷酸酶家族在ARDS急性肺损伤和全身炎性反应中的前哨作用 19.该项目的总体目标是改变KVX-053的用途，以对抗SARS-CoV-2 对于感染和未来涉及急性肺损伤的病毒大流行。此第一阶段SBIR应用程序有三个证明- 概念外特定任务。特殊任务1将确定一种新的、有效的、变构的小分子的能力 PTP4A抑制剂KVX-053阻断SARS-CoV-2 Spike 1蛋白介导的肺内皮细胞屏障丧失 体外功能和细胞因子的释放。具体任务2将确定KVX-053阻断SARS冠状病毒的能力- 2体外SPEKE-1蛋白介导的肺泡上皮屏障功能和细胞因子的释放。特定的 任务3将确定KVX-053抑制SARS-CoV-2尖峰病毒引起的小鼠急性肺损伤的能力 1蛋白质。

The Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) is responsible for the current COVID-19 pandemic. SAR-CoV-2, like other coronaviruses, infects human airways and enters cells via its S (Spike) protein, which binds to the human angiotensin-converting enzyme 2 (ACE2) and is primed by the host serine protease TMPRSS2. Both ACE2 and TMPRSS2 have been observed on pulmonary microvascular epithelium and endothelium. A subset of COVID-19 patients develop acute respiratory distress syndrome (ARDS) and subsequently septic shock and multi-organ failure; about half will die. The clinical worsening in the later phases of COVID-19 are thought to result from Spike protein binding to the pulmonary microvascular endothelium and epithelium, which leads to a damaged respiratory tract and ultimately a systemic inflammatory response or cytokine storm. There are currently no FDA-approved drugs/therapeutics that treat the pulmonary damage and ARDS associated with COVID-19. KeViRx is proposing to develop an entirely new therapeutic strategy that prevents or mitigates the initial pulmonary damage and halts the lethal cytokine storm. Our lead compound, KVX-053, is a reversible, selective, allosteric inhibitor of PTP4A3 phosphatase with excellent in vivo pharmacokinetic properties and drug-like properties. Moreover, mice tolerated multiple exposures to KVX-053. In culture KVX-053 was not cytotoxic to human ovarian epithelial cells or fibroblasts at concentrations up to 25 µM. Surprisingly, we found that KVX-053 markedly enhanced the pulmonary microvascular barrier function before and after injury caused by bacterial lipopolysaccharide and vascular endothelial growth factor. PTP4A3 phosphatase is known to be induced in lung cells 12 h after SARS-CoV infection and to control cytokine release. The overall hypothesis of this Phase I SBIR application is that the PTP4A phosphatase family has a sentinel role in the acute lung injury of ARDS and the systemic inflammatory response in COVID-19.The overall goal of the project is to repurpose KVX-053 for use against SARS-CoV-2 infection and for future viral pandemics involving acute lung injury. This Phase I SBIR application has three proof- of-concept Specific Tasks. Specific Task 1 will determine the ability of a novel, potent, allosteric, small molecule PTP4A inhibitor, KVX-053, to block SARS-CoV-2 Spike 1 protein-mediated loss of pulmonary endothelial barrier function and cytokine release in vitro. Specific Task 2 will determine the ability of KVX-053 to block SARS-CoV- 2 Spike 1 protein-mediated pulmonary alveolar epithelial barrier function and cytokine release in vitro. Specific Task 3 will determine the ability of KVX-053 to inhibit acute lung injury in mice caused by the SARS-CoV-2 Spike 1 protein.